Targeting the AnxA1/Fpr2/ALX pathway regulates neutrophil function, promoting thromboinflammation resolution in sickle cell disease.
Adaptor Proteins, Signal Transducing
/ metabolism
Adult
Anemia, Sickle Cell
/ complications
Animals
Annexin A1
/ metabolism
Female
Humans
Inflammation
/ etiology
Male
Mice
Middle Aged
Neutrophils
/ metabolism
Receptors, Formyl Peptide
/ metabolism
Receptors, Lipoxin
/ metabolism
Signal Transduction
Thrombosis
/ etiology
Young Adult
Journal
Blood
ISSN: 1528-0020
Titre abrégé: Blood
Pays: United States
ID NLM: 7603509
Informations de publication
Date de publication:
18 03 2021
18 03 2021
Historique:
received:
15
09
2020
accepted:
28
12
2020
pubmed:
30
1
2021
medline:
28
8
2021
entrez:
29
1
2021
Statut:
ppublish
Résumé
Neutrophils play a crucial role in the intertwined processes of thrombosis and inflammation. An altered neutrophil phenotype may contribute to inadequate resolution, which is known to be a major pathophysiological contributor of thromboinflammatory conditions such as sickle cell disease (SCD). The endogenous protein annexin A1 (AnxA1) facilitates inflammation resolution via formyl peptide receptors (FPRs). We sought to comprehensively elucidate the functional significance of targeting the neutrophil-dependent AnxA1/FPR2/ALX pathway in SCD. Administration of AnxA1 mimetic peptide AnxA1Ac2-26 ameliorated cerebral thrombotic responses in Sickle transgenic mice via regulation of the FPR2/ALX (a fundamental receptor involved in resolution) pathway. We found direct evidence that neutrophils with SCD phenotype play a key role in contributing to thromboinflammation. In addition, AnxA1Ac2-26 regulated activated SCD neutrophils through protein kinase B (Akt) and extracellular signal-regulated kinases (ERK1/2) to enable resolution. We present compelling conceptual evidence that targeting the AnxA1/FPR2/ALX pathway may provide new therapeutic possibilities against thromboinflammatory conditions such as SCD.
Identifiants
pubmed: 33512489
pii: S0006-4971(21)00182-8
doi: 10.1182/blood.2020009166
pmc: PMC7976506
doi:
Substances chimiques
ANXA1 protein, human
0
Adaptor Proteins, Signal Transducing
0
Annexin A1
0
FPR2 protein, human
0
HSH2D protein, human
0
Receptors, Formyl Peptide
0
Receptors, Lipoxin
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1538-1549Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL098435
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL133497
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL141155
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2021 by The American Society of Hematology.
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